Process for the preparation of stable acid addition salt of 2,3-disubstituted pyrazine compounds

ABSTRACT

The present invention relates to a process for the preparation of compounds which are therapeutically active in the central nervous system. 
     In one aspect, the invention relates to a process for the preparation of compounds of the general formula (I): 
                         
wherein HA is a pharmaceutically acceptable acid and R 1 –R 4  are each independently selected from the group consisting of hydrogen, halogen, C 1 –C 6 -alkyl, C 1 –C 6 -alkoxy, and di-C 1 –C 6 -alkylamino-C 2 –C 6 -alkoxy.
 
     The invention also relates to the use of said compound to manufacture a medicament for the treatment of a serotonin-related disorder.

RELATED APPLICATIONS

This application claims priority to Swedish application number0201881-0, filed on Jun. 19, 2002, Swedish application number 0202041-0,filed on Jun. 28, 2002, Swedish application number 0202516-1, filed onAug. 26, 2002, U.S. provisional application No. 60/390,656, filed Jun.21, 2002, U.S. provisional application No. 60/406,119, filed on Aug. 26,2002, and U.S. provisional application No. 60/416,701, filed on Oct. 7,2002, the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation ofcompounds which are therapeutically active in the central nervoussystem.

BACKGROUND OF THE INVENTION

Many diseases of the central nervous system are influenced by theadrenergic, the dopaminergic, and the serotonergic neurotransmittersystems. For example, serotonin has been implicated in a number ofdiseases and conditions which originate in the central nervous system. Anumber of pharmacological and genetic experiments involving receptorsfor serotonin strongly implicate the 5-HT_(2c) receptor subtype in theregulation of food intake (Obes. Res. 1995, 3, Suppl. 4, 449S–462S). The5-HT_(2c) receptor subtype is transcribed and expressed in hypothalamicstructures associated with appetite regulation. It has been demonstratedthat the non-specific 5-HT_(2c) receptor agonistm-chlorophenylpiperazine (mCPP), which has some preference for the5-HT_(2c) receptor, causes weight loss in mice that express the normal5-HT_(2c) receptor while the compound lacks activity in mice expressingthe mutated inactive form of the 5-HT_(2c) receptor (Nature 1995, 374,542–546). In a recent clinical study, a slight but sustained reductionin body weight was obtained after 2 weeks of treatment with mCPP inobese subjects (Psychopharmacology 1997, 133, 309–312). Weight reductionhas also been reported from clinical studies with other “serotonergic”agents (see e.g. IDrugs 1998, 1, 456–470). For example, the 5-HTreuptake inhibitor fluoxetine and the 5-HT releasing agent/reuptakeinhibitor dexfenfluramine have exhibited weight reduction in controlledstudies. However, currently available drugs that increase serotonergictransmission appear to have only a moderate and, in some cases,transient effects on the body weight.

The 5-HT_(2c) receptor subtype has also been suggested to be involved inCNS disorders such as depression and anxiety (Exp. Opin. Invest. Drugs1998, 7, 1587–1599; IDrugs, 1999, 2, 109–120).

The 5-HT_(2c) receptor subtype has further been suggested to be involvedin urinary disorders such as urinary incontinence (IDrugs, 1999, 2,109–120).

Compounds which have a selective effect on the 5-HT_(2c) receptor maytherefore have a therapeutic potential in the treatment or prophylaxisof disorders like those mentioned above. Of course, selectivity alsoreduces the potential for adverse effects mediated by other serotoninreceptors.

Examples of such compounds are(2R)-1-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,(2R)-methyl-1-{3-[2-(3-pyridinyloxy]ethoxy]-2-pyrazinyl}piperazine andpharmaceutically acceptable acid salts thereof. WO 00/76984 (hereinaftercalled D1) relates to a process for the preparation of such compounds ona small scale such as a gram scale. A problem to be solved by thepresent invention was to prepare such compounds on a large scale such ason a kilogram scale. The following factors are more important forpreparation on a large scale, in comparison to preparation on a smallscale:

-   to obtain a high yield of the desired products for economy reasons,-   that the processes for preparation are safe with regard to    explosion,-   that the reagents and solvents used are relatively non-toxic,-   that the products obtained are relatively stable, and-   that the reaction times are relatively short.    These problems have been solved by the present invention. It has    been shown that the yields of the desired products according to the    present invention are higher than the yields according to D1. In the    experimental part, the yields according to the present invention and    D1 are compared. Regarding the choice of solvents for the process    steps, dioxane, as used according to D1, has been replaced by    solvents such as MtBE and THF (see step (ii) below) which are less    prone to form peroxides and which are less carcinogenic than    dioxane. Furthermore, it has been shown that    (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    L-malate salt prepared according to the present invention (see    Example 3A) has superior properties compared to    (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    hydrochloride prepared according to D1 in that the former has a    higher crystallinity, is less hygroscopic and has a higher chemical    stability than the latter. Regarding chemical stability, D1    discloses the preparation of    (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine, which has also    been prepared in Example 8 below. This compound is not stable for    storage as a free base. As    (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine is a key    intermediate, chemical stability during long term storage is    important with regard to process economy. It has now been found that    the corresponding hydrochloride salt thereof is considerably more    stable, which has been prepared in Example 9 below.

The method to prepare Example 3C is a good way of increasing the purityof Example 2C. It has been shown that Example 2C with a purity of 60–70%gives Example 3C with a purity of 99% in one crystallization step. Bycontrast, the same purity increasing effect has not been achieved bymaking the acetate of Example 2C. Regarding reaction time, the reactionaccording to Example 2A below was complete at room temperature in 15minutes. The same compound has been prepared in Example 173 in D 1. Theprocedure of Example 172, step 3 has been followed, wherein the reactionwas stirred at 85° C. for 15 h. Furthermore, the reaction according toExample 2B below was complete in 35 minutes at 55° C. The same compoundhas been prepared in Example 200 in D1. The procedure of Example 192,step 3 has been followed, wherein the reaction was stirred at 90° C. for2 h.

SUMMARY OF THE INVENTION

One object of the present invention is a process for the preparation ofcompounds which bind to the 5-HT_(2c) receptor (agonists andantagonists) and which therefore may be used for the treatment orprophylaxis of serotonin-related disorders.

In one aspect, the invention relates to a process for the preparation ofcompounds of the general formula (I):

comprising the steps of:

-   (i) hydroxyalkylating (i.e., O-alkylating) a 3-pyridinol derivative    of the general formula (II) or the corresponding hydrochloride:

to give another 3-pyridinol derivative of the general formula (III):

-   (ii) condensing the 3-pyridinol derivative of the general    formula (III) with (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpyrazine of    the formula (IV) in the presence of an alkali metal tert-butoxide    (e.g. potassium tert-butoxide) or an alkali earth metal    tert-butoxide, as a base in a solvent system (e.g., a solvent system    containing tetrahydrofuran),

to give a compound of the general formula (V):

-   (iii) which is then converted to the compound of the general    formula (I) by treatment with a pharmaceutically acceptable acid of    the formula HA,    wherein-   R₁–R₄ are each independently selected from the group consisting of    hydrogen, halogen, C₁–C₆-alkyl, C₁–C₆-alkoxy, and    di-C₁–C₆-alkylamino-C₂–C₆-alkoxy; and wherein-   (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpyrazine of the formula (IV)    is prepared by:-   (iv) acidification of racemic 2-methylpiperazine of the formula    (VI):

with L-tartaric acid and fractional crystallization to give(R)-2-methylpiperazine, L-tartrate of the formula (VII):

-   (v) basification of (2R)-2-methylpiperazine, L-tartrate of the    formula (VII) to give (R)-2-methylpiperazine of the formula (VIII):

-   (vi) tritylation of (R)-2-methylpiperazine of the formula (VIII) to    give (R)-3-methyl-1-tritylpiperazine of the formula (IX):

-   (vii) condensation of (R)-3-methyl-1-tritylpiperazine of the    formula (IX) with 2,3-dichloropyrazine to give    (2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine of the    formula (X):

-   (viii) detritylation of    (2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine of the    formula (X) to give (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine    of the formula (IV),-   (ix) and conversion of    (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV)    to a suitable acid addition salt (e.g, hydrochloride salt).

It is preferred that R₁–R₃ are hydrogen and R₄ is selected from thegroup consisting of hydrogen, ethoxy, and 2-dimethylaminoethoxy.

It is also preferred that:

-   step (iv) is performed by using water and ethanol as solvents;-   step (v) is performed by using a hydroxide (e.g., sodium hydroxide)    as a base;-   step (vi) is performed with trityl chloride in the presence of    triethylamine;-   step (vii) is performed in the presence of an alkali metal carbonate    (e.g. potassium carbonate) or an alkali earth metal carbonate, with    dimethyl formamide as a solvent; and-   step (viii) is performed in 10% sulfuric acid in isopropanol.

When R₁–R₄ are hydrogen, it is preferred that:

-   step (i) is performed by reacting the compound of the formula (II)    with ethylene carbonate with an alkali metal carbonate (e.g.    potassium carbonate) or an alkali earth metal carbonate, as a base    and dimethyl formamide as a solvent,-   step (ii) is performed by reacting the compound of the formula (III)    with the compound of the formula (IV) in the presence of an alkali    metal tert-butoxide (e.g. potassium tert-butoxide) or an alkali    earth metal tert-butoxide, in tetrahydrofuran,-   the pharmaceutically acceptable acid of the formula HA in step (iii)    is L-malic acid.    Before converting the compound of the formula (I), wherein R₁–R₄ are    hydrogen, into the L-malate salt, the product of the formula (V) is    preferably converted to the fumarate, giving a more pure product.    After that, the fumarate may be converted to the L-malate, e.g. via    neutralization of the fumarate with a base and then converted to the    L-malate by means of L-malic acid.

When R₁–R₃ are hydrogen and R₄ is ethoxy, it is preferred that:

-   step (i) is performed by reacting the hydrochloride of the compound    of the formula (II) with 2-chloroethanol with in an aqueous solution    of a hydroxide, more preferably sodium hydroxide,-   step (ii) is performed by reacting the compound of the formula (III)    with the compound of the formula (IV) in the presence of an alkali    metal tert-butoxide (e.g. potassium tert-butoxide) or an alkali    earth metal tert-butoxide, in a solvent system consisting of methyl    tert-butylether and tetrahydrofuran,-   the pharmaceutically acceptable acid of the formula HA in step (iii)    is succinic acid.

When R₁–R₃ are hydrogen and R₄ is 2-dimethylaminoethoxy, it is preferredthat:

-   step (i) is performed by reacting the compound of the formula (II)    with ethylene carbonate with an alkali metal carbonate (e.g.    potassium carbonate) or an alkali earth metal carbonate, as a base    and dimethyl sulfoxide as a solvent,-   step (ii) is performed by reacting the compound of the formula (III)    with the compound of the formula (IV) in the presence of an alkali    metal tert-butoxide (e.g. potassium tert-butoxide) or an alkali    earth metal tert-butoxide, in tetrahydrofuran,-   the pharmaceutically acceptable acid of the formula HA in step (iii)    is phosphoric acid.

This invention also features a process for the preparation of compoundsof the general formula (I). The process includes the steps of:

-   (i) reacting a 3-pyridinol derivative of the general formula (II) or    the corresponding hydrochloride with ethylene carbonate, to give    another 3-pyridinol derivative of the general formula (III):-   (ii) reacting the 3-pyridinol derivative of the general    formula (III) with (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine    of the formula (IV) in the presence of an alkali metal tert-butoxide    (e.g., potassium tert-butoxide) or an alkali earth metal    tert-butoxide, to give a compound of the general formula (V),-   (iii) converting the compound of the general formula (V) to the    compund of the general formula (I) by treatment with a    pharmaceutically acceptable acid of the formula HA (e.g., L-malic    acid),    wherein each of R₁, R₂, R₃, and R₄ is hydrogen. Step (i) can be    performed in the presence of an alkali metal carbonate (e.g.    potassium carbonate) or an alkali earth metal carbonate as a base,    and dimethyl formamide as a solvent; and step (ii) can be performed    by reacting the compound of the general formula (III) with the    compound of the formula (IV) in tetrahydrofuran.

In this process, (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of theformula (IV) can be prepared by:

-   (iv) acidification of racemic 2-methylpiperazine of the formula (VI)    with L-tartaric acid and fractional crystallization to give    (R)-2-methylpiperazine, L-tartrate of the formula (VII):-   (v) basification of (2R)-2-methylpiperazine, L-tartrate of the    formula (VII) to give (R)-2-methylpiperazine of the formula (VIII):-   (vi) tritylation of (R)-2-methylpiperazine of the formula (VIII) to    give (R)-3-methyl-1-tritylpiperazine of the formula (IX),-   (vii) condensation of (R)-3-methyl-1-tritylpiperazine of the    formula (IX) with 2,3-dichloropyrazine to give    (2R)-1-(3-chloro-2-pyrazine)-2-methyl-4-tritylpiperazine of the    formula (X):-   (viii) detritylation of    (2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine of the    formula (X) to give (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine    of the formula (IV),-   (ix) and conversion of    (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV)    to a suitable acid addition salt (e.g, hydrochloride salt).    The formula (I) to (X) are the same as described above.

This invention further features a process for the preparation ofcompounds of the general formula (I). The process includes the steps of:

-   (i) O-alkylating a 3-pyridinol derivative of the general    formula (II) or the corresponding hydrochloride, to give another    3-pyridinol derivative of the general formula (III),-   (ii) reacting the 3-pyridinol derivative of the general    formula (III) with (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine    of the formula (IV) in the presence of potassium tert-butoxide, to    give a compound of the general formula (V),-   (iii) converting the compound of the general formula (V) to the    compound of the general formula (I) by treatment with a    pharmaceutically acceptable acid of the formula HA (e.g., succinic    acid),    wherein each of R₁, R₂, and R₃ is hydrogen, R₄ is C₁–C₆-alkoxy    (e.g., ethoxy). Step (i) can be performed by reacting the    hydrochloride of the compound of the general formula (II) with    2-chloroethanol in an aqueous solution of a hydroxide (e.g., sodium    hydroxide), and step (ii) can be performed by reacting the compound    of the general formula (III) with the compound of the formula (IV)    in a solvent system consisting of methyl tert-butylether and    tetrahydrofuran.

This invention also features a process for the preparation of compoundsof the general formula (I). The process includes the steps of:

-   (i) reacting a 3-pyridinol derivative of the general formula (II) or    the corresponding hydrochloride with ethylene carbonate, to give    another 3-pyridinol derivative of the general formula (III):-   (ii) reacting the 3-pyridinol derivative of the general    formula (III) with (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine    of the formula (IV) in the presence of an alkali metal tert-butoxide    (e.g., potassium tert-butoxide) or an alkali earth metal    tert-butoxide, to give a compound of the general formula (V),-   (iii) converting the compound of the general formula (V) to the    compund of the general formula (I) by treatment with a    pharmaceutically acceptable acid of the formula HA (e.g., phosphoric    acid),    wherein each of R₁, R₂, and R₃ is hydrogen, R₄ is    di-C₁–C₆-alkylamino-C₂–C₆-alkoxy (e.g., 2-dimethylaminoethoxy).    Step (i) can be performed in the presence of an alkali metal    carbonate (e.g. potassium carbonate) or an alkali earth metal    carbonate as a base, and dimethyl sulfoxide as a solvent; and    step (ii) can be performed by reacting the compound of the general    formula (III) with the compound of the formula (IV) in    tetrahydrofuran.

Another object of the present invention is a process for preparing(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine, hydrochloride byreacting (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula(IV) with hydrochloric acid.

Another object of the present invention is the compound(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine, hydrochloride.

Another object of the present invention is a compound of the formula(I), wherein R₁–R₄ are hydrogen and HA is L-malic acid.

Another object of the present invention is a compound of the formula(I), wherein R₁–R₃ are hydrogen, R₄ is ethoxy and HA is succinic acid.Another object of the present invention is a compound of the formula(I), wherein R₁–R₃ are hydrogen, R₄ is 2-dimethylaminoethoxy, and HA isphosphoric acid.

Also within the scope of this invention is a method for the treatment orprophylaxis of a serotonin-related disorder, particularly 5-HT_(2c)receptor related. The method includes administering to a subject in needthereof an effective amount of a compound of the formula (I), whereinR₁–R₃ are hydrogen, R₄ is selected from hydrogen, ethoxy, and2-dimethylaminoethoxy, and HA is selected from L-malic acid, succinicacid, and phosphoric acid. Examples of such disorders are obesity andtype II diabetes.

Also within the scope of this invention is the use of a compound offormula (I), wherein R₁–R₃ are hydrogen, R₄ is selected from hydrogen,ethoxy, and 2-dimethylaminoethoxy, and HA is selected from L-malic acid,succinic acid, and phosphoric acid, to manufacture a medicament for thetreatment or prophylaxis of a serotonin-related disorder, particularly5-HT_(2c) receptor related. Examples of such disorders are obesity andtype II diabetes.

Another aspect is a method of making a composition comprising combininga compound of formula (I) (including those made by the processesdelineated herein) with a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

Below, the various terms used in the above definition of the compoundsof the compounds of the general formulas (I)–(V) will be explained.

C₁–C₆-alkyl is a straight or branched alkyl group having 1–6 carbonatoms. Exemplary alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl,and isohexyl.

For parts of the range “C₁–C₆-alkyl” all subgroups thereof arecontemplated such as C₁–C₅-alkyl, C₁–C₄-alkyl, C₁–C₃-alkyl, C₁–C₂-alkyl,C₂–C₆-alkyl, C₂–C₅-alkyl, C₂–C₄-alkyl, C₂–C₃-alkyl, C₃–C₆-alkyl,C₄–C₅-alkyl, etc.

C₁–C₆-alkoxy is a straight or branched alkyl group having 1–6 carbonatoms. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy,n-hexoxy, and isohexoxy.

For parts of the range “C₁–C₆-alkoxy” all subgroups thereof arecontemplated such as C₁–C₅-alkoxy, C₁–C₄-alkoxy, C₁–C₃-alkoxy,C₁–C₂-alkoxy, C₂–C₆-alkoxy, C₂–C₅-alkoxy, C₂–C₄-alkoxy, C₂–C₃-alkoxy,C₃–C₆-alkoxy, C₄–C₅-alkoxy, etc.

The term “DSC” in the present description means “differential scanningcalorimetry”.

The term “DVS” in the present description means “dynamic vapor sorptiongravimetry”.

The term “FBE” in the present description means “free base equivalents”.

The term “halogen” in the present description is intended to includefluorine, chlorine, bromine and iodine.

The term “IDR” in the present description means “intrinsic dissolutionrate”.

The term “IP” in the present description means “in process”.

The term “NLT” in the present description means “not less than”.

“Pharmaceutically acceptable acid salts” mean salts which arepharmaceutically acceptable, as defined above, and which possess thedesired pharmacological activity. Such salts include acid addition saltsformed with any organic and inorganic pharmaceutically acceptable acid(“HA”), such as hydrogen chloride, hydrogen bromide, hydrogen iodide,sulfuric acid, phosphoric acid, acetic acid, glycolic acid, maleic acid,malonic acid, oxalic acid, toluenesulfonic acid, methanesulfonic acid,trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaricacid, citric acid, benzoic acid, ascorbic acid and the like.

DMF means dimethyl formamide, DMSO means dimethyl sulfoxide, IPA meansisopropanol, MtBE means methyl tert-butyl ether, RH means relativehumidity, RT means room temperature, t-BuOK means tert-butyl alcohol,potassium salt, THF means tetrahydrofuran, and trityl meanstriphenylmethyl.

It should be noted that both E- and Z-isomers of the compounds, opticalisomers, as well as mixtures thereof, and all isotopes are includedwithin the scope of the invention. By the expression “isotopes” is meantall compounds with naturally occurring isotopes such as all possibledeuterium and ¹³C-isotopes of the compounds according to the invention.The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstituted such compounds. For example, the compounds may beradiolabelled with radioactive isotopes, such as fore example tritium(³H), ¹²⁵I or ¹⁴C. All isotopic variations of the compounds of thepresent invention, whether radioactive or not, are intended to beencompassed within the scope of the present invention.

The chemicals used in the above-described synthetic routes may include,for example, solvents, reagents, catalysts, protecting group anddeprotecting group agents. The methods described above may alsoadditionally include steps, either before or after the steps describedspecifically herein, to add or remove suitable protecting groups inorder to ultimately allow synthesis of the compounds of the formula (I).Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing applicablecompounds of the formula (I) are known in the art and include, forexample, those described in R. Larock, Comprehensive OrganicTransformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts,Protective Groups in Organic Synthesis, 2^(nd) Ed., John Wiley and Sons(1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents forOrganic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.,Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons(1995) and subsequent editions thereof.

In accordance with the present invention, the compound of the formula(I), wherein R₁–R₃ are hydrogen, R₄ is selected from hydrogen, ethoxy or2-dimethylaminoethoxy and HA is selected from L-malic acid, succinicacid, and phosphoric acid, can be brought into suitable galenic forms,such as compositions for oral use, for injection, for nasal sprayadministration or the like, in accordance with accepted pharmaceuticalprocedures. Such pharmaceutical compositions according to the inventioncomprise an effective amount of the aforementioned compound inassociation with compatible pharmaceutically acceptable carriermaterials, or diluents, as are well known in the art. The carriers maybe any inert material, organic or inorganic, suitable for enteral,percutaneous, subcutaneous or parenteral administration, such as: water,gelatin, gum arabicum, lactose, microcrystalline cellulose, starch,sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate,talcum, colloidal silicon dioxide, and the like. Such compositions mayalso contain other pharmacologically active agents, and conventionaladditives, such as stabilizers, wetting agents, emulsifiers, flavouringagents, buffers, and the like.

The compositions according to the invention can e.g. be made up in solidor liquid form for oral administration, such as tablets, pills,capsules, powders, syrups, elixirs, dispersable granules, cachets,suppositories and the like, in the form of sterile solutions,suspensions or emulsions for parenteral administration, sprays, e.g. anasal spray, transdermal preparations, e.g. patches, and the like.

As mentioned above, the aforementioned compounds of the invention may beused for the treatment or prophylaxis of a subject (e.g., a human or ananimal) suffering from a serotonin-related disorder or conditions,particularly 5-HT_(2c) receptor related, such as memory disorders, suchas Alzheimer's disease; schizophrenia; mood disorders such asdepression; anxiety disorders; pain; substance abuse; sexualdysfunctions such as erectile dysfunction; epilepsy; glaucoma; urinarydisorders, such as urinary incontinence; menopausal and post-menopausalhot flushes; eating disorders, such as binge eating disorders, anorexianervosa and bulimia; weight gain associated with antipsychotic drugadministration, type II diabetes; and particularly obesity.

The method of treatment or prophylaxis includes administrering to asubject in need of treatment an effective amount of the compound of thisinvention. The term “treating” or “treated” refers to administering acompound of this invention to a subject with the purpose to cure, heal,alleviate, relieve, alter, remedy, ameliorate, improve, or affect adisease, the symptoms of the disease or the predisposition toward thedisease. “An effective amount” refers to an amount of a compound whichconfers a therapeutic effect on the treated subject. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect).The dose level and frequency of dosage of the specific compound willvary depending on a variety of factors including the potency of thespecific compound employed, the metabolic stability and length of actionof that compound, the patient's age, body weight, general health, sex,diet, mode and time of administration, rate of excretion, drugcombination, the severity of the condition to be treated, and thepatient undergoing therapy. The daily dosage may, for example, rangefrom about 0.001 mg to about 100 mg per kilo of body weight,administered singly or multiply in doses, e.g. from about 0.01 mg toabout 25 mg each. Normally, such a dosage is given orally but parenteraladministration may also be chosen.

The invention also refers to the use of the aforementioned compounds tomanufacture a medicament for the treatment or prophylaxis of aserotonin-related disorder, particularly 5-HT_(2c) receptor related.

All publications mentioned herein are hereby incorporated by reference.By the expression “comprising” we understand including but not limitedto.

The invention will now be illuminated by the following Examples, whichare only intended to illuminate and not restrict the invention in anyway. Examples 1A–3A illustrate steps (i)–(iii) when R₁–R₄ are hydrogen.Examples 1B–3B illustrate steps (i)–(iii) when R₁–R₃ are hydrogen and R₄is ethoxy. Examples 1C–3C illustrate steps (i)–(iii) when R₁–R₃ arehydrogen and R₄ is 2-dimethylaminoethoxy. Examples 4–8 illustrate steps(iv)–(viii) when R₁–R₃ are hydrogen and R₄ is selected from the groupconsisting of hydrogen, ethoxy, and 2-dimethylaminoethoxy. Regarding thecompound of the formula (IV) as prepared in step (viii), it has beenshown that this compound is not stable for storage as a free base.However, the corresponding hydrochloride thereof is considerably morestable. Example 9 describes the preparation of(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine, hydrochloride.Furthermore, the properties of different salts of the formula (I) wereevaluated. Example 10 describes the preparation of(2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,fumarate. By making the fumarate in Example 10, a more pure product isobtained before converting to the L-malate salt (prepared in Example3A). Example 11 describes the comparison of the properties of differentsalts of Example 2A. Example 12 describes the comparison of theproperties of different salts of Example 2B. Example 13 describes thecomparison of the properties of different salts of Example 2C.

EXAMPLES

General

2-ethoxy-3-hydroxypyridine, HCl (for Example 1B) and2-(2-dimethylaminoethoxy)pyridin-3-ol (for Example 1C) were purchasedfrom Nordic Synthesis in Karlskoga, Sweden. The other chemicalsmentioned are commercially available and could e g be purchased fromAldrich. For Examples 1B–3B, HPLC analysis confirmed that the desiredproducts were obtained. The HPLC pump was a Varian 9012. A Varian 9050detector at 220 nm was used. The eluent was 80 mM KH₂PO₄ in a 80:20mixture of water/acetonitrile. The column was a Varian C8, 150×4.5 mm.For Examples, 1C–3C, HPLC analysis also confirmed that the desiredproducts were obtained. The eluent was A: 0.1% trifluoroacetic acid inwater, B: acetonitrile; increasing percentage of acetonitrile during 3minutes. The column was a YMC FL-ODS AQ S-5μ, 12 nm, 50×4.6 mm (Example1C) and a Hypersil BDS C18, 3μ, 30×4.6 mm (Example 2C–3C), respectively.

Example 1A Preparation of 2-(3-pyridinyloxy)ethanol

3-hydroxypyridine (20.0 kg), ethylene carbonate (19.4 kg), K₂CO₃ (18.9kg), and DMF (75.5 kg) were charged to a 400 L reactor and heated to 86°C. After 13 h, an aliquot was taken. There was still some3-hydroxypyridine left by GC so more ethylene carbonate (1.0 kg) wasadded. After 20 h, the reaction was deemed complete. The reaction wascooled to 20° C., H₂O (85 L) was slowly added to the 400 L reactor, andstirring continued for 30 min. The title compound was extracted with 35°C. CH₂Cl₂ (4×170 L) sending the CH₂Cl₂ extractions into the 1000 Lportable tank. The aqueous layer was discarded, and the 400 L reactorwas cleaned. The solution of the title compound in the 1000 L portabletank was transferred to the 400 L and distilled in the 400 L reactorsending the distillate to the 400 L receiver. Toluene (200 L) was addedto the 400 L reactor and distilled sending the distillate to the 400 Lreceiver. The resulting oil was transferred to a 20 L glass bottle toproduce 21.0 kg (72%) of the title compound of 100.0% GC purity.

The yield of the title compound according to D1, starting from3-hydroxypyridine, 2-chloroethanol and K₂CO₃ in DMF was 19%. The titlecompound has also been prepared according to EP 0 286 242 A2 startingfrom methyl [(3-pyridinyl)oxy]acetate.

¹H NMR (400 MHz, CDCl₃): δ 8.30 (1H, br s), 8.20 (1H, t, J=3.1 Hz), 7.23(2H, t, J=2.1 Hz), 4.13 (2H, t, J=4.6 Hz), 3.99 (2H, t, J=4.6 Hz), 3.76(1H, br s), 0.00 (TMS, reference).

¹³C NMR (100 MHz, CDCl₃): δ 155.09 (s), 142.09 (d), 137.95 (d), 123.99(d), 121.32 (d), 69.83 (t), 60.98 (t), 0.00 (TMS, reference).

IR (liq.) 2382 (w), 2082 (w), 1996 (w), 1954 (w), 1587, 1576 (s), 1488,1478 (s), 1429 (s), 1272 (s), 1235 (s), 1084, 1054 (s), 802, 707 (s),cm⁻¹.

Anal. Calcd for C₇H₉NO₂: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.14;H, 6.51; N, 10.39.

HRMS (FAB) calcd for C₇H₉NO₂+H₁ 140.0712, found 140.0705.

Example 1B Preparation of 2-[(2-ethoxy-3-pyridinyl)oxy]ethanol

To water (30.0 kg) was added 3.40 kg of NaOH. The resulting suspensionwas stirred until complete dissolution had occurred. The temperature ofthe solution was then adjusted to approx. 60° C. To the alkalinesolution was carefully added 2-ethoxy-3-hydroxypyridine, HCl (6.00 kg).The temperature was raised to 85.0° C. and the mixture stirred for 30min to allow for complete dissolution. During 85 min, 2-chloroethanol(4.10 kg) was added, while the temperature was kept between 88.0–92.0°C. The reaction was allowed to age for 50 min at approx. 90° C., afterwhich time HPLC indicated complete conversion of2-ethoxy-3-hydroxypyridine, HCl to the title compound. The reactionmixture was poured into 65.1 kg of methyl tert-butylether (MtBE). Thereaction vessel was rinsed with water (2.0 kg). To the resultingtwo-phase system was added 3.05 kg of NaCl and 0.20 kg of NaOH. Theresulting mixture was stirred for 55 min, while the temperature waslowered to 24.9° C. The mixture was the allowed to stir for another 20min at 23.7–24.9° C. The water phase was removed. The remaining organicphase was concentrated by distillation at atmospheric pressure. When 45L had been removed, the residue was cooled to room temperature andtransferred to a drum. The residue weighed 33.1 kg. According to HPLC,the assay is 118.9 g of the title compound per kg of mixture,corresponding to a yield of 6.25 kg (quantitative yield) of pure titlecompound.

The yield of the title compound according to Dl, starting from2-bromo-3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)pyridine and sodiumethoxide in ethanol was 41%.

Example 1C Preparation of2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethanol

DMSO (17 L) and potassium carbonate (8.2 kg) were charged to the 100L-glasslined reactor. The mixture was heated to 58° C. while stirring.2-(2-Dimethylaminoethoxy)pyridin-3-ol (4.11 kg) was charged to thereactor during 25 minutes (gas evolution). The mixture was heated to117° C. before the prepared ethylene carbonate solution was addedthrough the manhood in portions. After 1 L ethylene carbonate solutionwas added IP-HPLC was taken to ensure that the title compound hadstarted to form. The total addition of ethylene carbonate solution wasmade during 1 h 35 minutes. Temperature after the addition was 124° C. AHPLC sample was taken from the reaction mixture 10 minutes afterfinished addition. It showed 95% conversion to product. Thereaction-mixture was allowed to cool to 70° C. before water (45 L) andsodium chloride (4.06 kg) was charged to the reactor. The mixture wasthen stirred for 20 minutes at 70° C. before cooled to RT. Ethyl acetate(137 L) was charged into a 328 L glass-lined reactor. The water mixturewas transferred from the 100 L reactor to the 328 L reactor. The mixturewas stirred for 25 minutes before the mechanical stirrer was turned off.After allowing the phases to separate for 40 minutes, the water-phase(65 L) was discharged. The mixture was heated to reflux and 102 L ofethyl acetate was distilled off. Toluene (72 L) was added and themixture was heated to reflux again and 61 L of toluene/ethyl acetate wasdistilled off. The reaction mixture was then cooled to RT. The titlecompound was never isolated; it was directly used in Example 2C.

The preparation of the title compound has not been described in D1.

Example 2A Preparation of(2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine

A 400 L reactor containing a toluene solution of(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (for preparation ofthis compound, see Example 8 below) was distilled to remove toluene. THF(40 kg) was added, and the slurry was stirred until all the oildissolved. The solution was transferred to a drum with a THF rinse (10kg). The THF/toluene solution of(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (ca 9.7 kg thereof in90.4 kg solution) was transferred to a 1200 L reactor with a THF rinse(4 L). 2-(3-pyridinyloxy)ethanol from Example 1A (7.6 kg) wastransferred to the 1200 L reactor with a THF rinse (34 L) and stirred atroom temperature for 15 min. 20 wt % KOt-Bu (33.3 kg) was added followedby a THF rinse (4 kg). The reaction was monitored by GC and was completein 15 min. The reaction in the 1200 L reactor was quenched with H₂O (119L) and extracted with CH₂Cl₂ (1×215 L, 2×117 L) sending the CH₂Cl₂extractions into the 800 L receiver. The CH₂Cl₂ solution was transferredto the 1200 L reactor and the CH₂Cl₂ was removed by distillation. Asolvent swap distillation using MeOH (2×215 L) was performed distillingto a volume of 100 L. The MeOH solution of the title compound wasfiltered through a bag filter containing carbon (5 kg) recycling thesolution four times from the 1200 L reactor to the 800 L receiver. Thesolution in the 800 L receiver was transferred to the 1200 L reactorwith a MeOH rinse (50 L). The solution was distilled to a final volumeof 70 L and transferred to a drum with a MeOH rinse (10 L) inpreparation for the compound in Example 3A. The yield was quantitative.

The yield of the hydrochloride of the title compound according to D1,starting from3-chloro-2-[4-tert-butoxycarbonyl-(2R)-methyl-1-piperazinyl]pyrazine and2-(3-pyridinyloxy)ethanol with potassium tert-butoxide in dioxane was31%.

¹H NMR (400 MHz, CDCl₃): δ 8.35 (1H, br s), 8.25 (1H, t, J=3.0 Hz), 7.74(1H, d, J=3.0 Hz), 7.49 (1H, d, J=2.5 Hz), 7.23 (2H, br t, J=2.3 Hz),4.76 (1H, dt, J=12.2, 4.8 Hz), 4.67 (1H, dt, J=11.7 Hz, 5.2 Hz),4.49–4.43 (1H, m), 4.40 (2H, t, J=4.8 Hz), 3.72 (1H, br d, J=12.8 Hz),3.27 (1H, td, J=11.7, 3.0 Hz), 3.06 (1H, dd, J=12.3, 3.6 Hz), 2.99 (1H,br d, J=12.2 Hz), 2.88 (1H, td, J 11.7, 3.4 Hz), 2.75 (1H, br d, J=12.3Hz), 1.72 (1H, br s), 1.19 (3H, d, J=6.6 Hz), 0.00 (TMS, reference).

¹³C NMR (100 MHz, CDCl₃): δ 154.86 (s), 150.35 (s), 147.30 (s), 142.60(d), 138.09 (d), 134.14 (d), 129.89 (d), 123.87 (d), 121.17 (d), 66.54(t), 63.97 (t), 50.86 (t), 49.52 (d), 46.22 (t), 42.78 (t), 14.26 (q),0.00 (TMS, reference).

IR (liq.) 2068 (w), 1996 (w), 1576 (s), 1528 (s), 1475 (s), 1430 (s),1330, 1276 (s), 1268 (s), 1246, 1208 (s), 1187 (s), 1181 (s), 1063, 708,cm⁻¹.

HRMS (FAB) calcd for C₁₆H₂₁N₅O₂+H₁ 316.1773, found 316.1777.

[α]²⁵ _(D)=−24° (c 0.92, water).

Anal. Calcd for C₁₆H₂₁N₅O₂: C, 60.94; H, 6.71; N, 22.21. Found: C,59.98; H, 6.73; N, 22.40.

Example 2B Preparation of(2R)-1-(3-[2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy]-2-pyrazinyl)-2-methylpiperazine

(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (9.00 kg) (see Example8 for preparation) was dissolved in 20.1 kg of water by stirring a roomtemperature for 25 min. Activated charcoal (0.50 kg) and celite (0.50kg) was added. The resulting suspension was stirred for 30 min at roomtemperature. The charcoal and celite was removed by filtration underpressure. The filtered water-phase was poured into 63.9 kg of MtBE(methyl tert-butylether). To the resulting two-phase system were addedNaOH (1.50 kg) and NaCl (4.40 kg). After stirring for 25 min at roomtemperature, the water phase was discarded. The remaining organic phasewas concentrated by distillation at atmospheric pressure. A total of 45L was removed. To the remaining content of the reactor was added anMtBE-solution of 2-[(2-ethoxy-3-pyridinyl)oxy]ethanol (one completebatch from Example 1B). The resulting mixture is concentrated bydistillation at atmospheric pressure. A total of 40 L was removed. Tothe residue, 40.8 kg of MtBE was added. Further concentration bydistillation was done with a total of 20 L being removed. A solution ofpotassium tert-butoxide (KtBuO) was made by suspending 2.96 kg of KtBuOin 13.1 kg of THF. After stirring for 30 min at room temperature almosteverything was in solution. After emptying the reactor, a secondsolution was made by in a similar way (3.02 kg of KtBuO to 13.0 kg ofTHF). The mixture of 2-[(2-ethoxy-3-pyridinyl)oxy]ethanol and(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine was heated to 51.0° C.To this mixture was added the solutions of KtBuO in THF. During theaddition, the temperature was kept between 50.7–55.6° C. The totaladdition time was 50 min. After aging for 35 min at 55° C., HPLCindicated that the reaction was complete. The reaction mixture wascooled to room temperature and 23.1 kg of water was cautiously addedwhile maintaining the temperature below 25° C. After stirring for 15 minat approx. 23° C., the water phase was discarded. The remaining organicphase was concentrated by distillation at atmospheric pressure. After 45L had been removed, heptane (38.0 kg) was added. Further distillationremoved 50 L, followed by addition of heptane (33.8 kg). By removinganother 30 L via distillation, all remaining MtBE had been removed fromthe heptane solution. To the residue, 20.8 kg of water was added and thetemperature raised to 72.8° C. After stirring for 15 min, the waterphase was removed at this temperature. The remaining solution wasconcentrated by distillation at atmospheric pressure. A total of 50 Lwas removed. The residue was cooled to 50.5° C. The solution was seededwith 5.0 g of the title compound to induce crystallization. Theresulting suspension was stirred at 51.5° C. for 35 min whilemaintaining maximum stirring speed. Cooling was then continued to 8.1°C. over night. The product was isolated via filtration under suction.The resulting product cake was washed with 11 L of heptane. The semi-drycake weighing 9.63 kg was dried at 40° C./vakuum. The dried productweighed 8.1 kg (66%).

The yield of the fumarate of the title compound according to D1,starting from (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine and2-[(2-ethoxy-3-pyridinyl)oxy]ethanol with sodium tert-butoxide indioxane was 17%.

Example 2C Preparation of(2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine

(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (20 L in toluenesolution; see Example 8 for preparation) and active charcoal (201 g) wasadded to the 328 L-reactor containing2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy} ethanol (Example 1C) intoluene solution. The mixture was stirred for 25 minutes beforetransferred to a through a GAF-filter (containing a Teflon filter bag)to a 250 L-stainless steel reactor. The mixture was heated to 100° C.before the prepared “THF/potassium tert-butoxide-solution” was added tothe reactor using a 50 L addition bowl. After 10 L “THF/potassiumtert-butoxide-solution” was added, an IP-HPLC was taken to ensure thatthe title compound had started to form. The total addition ofTHF/potassium tert-butoxide-solution was made during 2 h and 15 minutes.Water (21 L) and sodium chloride (1 kg) was added to a 198 L-glasslinedreactor. The salt was dissolved before the reaction mixture wastransferred from the 328 L-reactor and quenched into the 198 L-reactor.Toluene (10 L) was also transferred to make sure that noreaction-mixture was left in the hoses used for the transfer. Themixture was then heated to 70° C. before the mechanical stirrer wasturned off. The phases were allowed to separate for 30 minutes beforethe water phase (25 L) was discharged. The mixture was heated to refluxand toluene (10 L) was distilled off. Water (100 L) was added and themixture was heated to reflux again and 60 L of water was distilled off.The remaining solution was then cooled to RT. The title compound wasnever isolated; it was directly used in the next step (Example 3C). IPsample (HPLC) of the toluene mixture confirmed the retention time forthe desired product (t_(ret)=2.2 minutes).

The preparation of the title compound has not been described in D1.

Example 3A Preparation of(2R)-methyl-1-[3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl]piperazine,L-malate Salt

To a 120 L receiver was added(2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine fromExample 2A (4.09 kg) and MeOH (12.7 kg) with stirring for about 7 minuntil all substance had dissolved. The solution was transferred to the120 L reactor through an in-line filter followed by a MeOH (2 kg) rinse.The L-malic acid (1.79 kg) was added to the 120 L receiver followed byacetone (8.8 kg) with stirring for about 13 min until all the L-malicacid had dissolved. The solution was transferred to the 120 L reactorthrough an in-line filter followed by an acetone (2 kg) rinse. Thesolution in the 120 L reactor was cooled to 5° C. MtBE (25 kg) was addedto the 120 L receiver and slowly transferred through an in-line filterinto the 120 L reactor. The solution was stirred at 0° C. for 1 h andfiltered onto the 18″ nutsche sending the filtrate into the 120 Lreceiver. (Inspection showed little product in the nutsche; only smallamounts of oil were present.) MeOH (40 L) was added to the 18″ nutscheto dissolve the oil. The MeOH solution and the filtrate in 120 Lreceiver were transferred through an in-line filter into 120 L reactorand the solution was distilled to a solid sending the distillate to the120 L receiver, which was disposed. MeOH (I 5 kg) was added through anin-line filter to 120 L reactor. The solution in 120 L reactor wasdistilled atmospherically replacing the MeOH with EtOH (35 kg) to avolume of 15 L. The solution was cooled to 58.6° C., seeded with 10 g of(2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,L-malate salt, and cooling continued to 25° C. Stirring was continuedfor 24 h, and the resulting slurry was filtered onto the 18″ nutschesending the filtrate into the 120 L receiver. The filter cake on the 18″nutsche was rinsed with filtered EtOH (15 kg) sending the rinse into the120 L receiver. The title compound was dried under vacuum using 60° C.nitrogen, deagglomerated, and packaged to yield 3.58 kg (61%) of thetitle compound of 98.61% GC purity.

The preparation of the title compound has not been described in D1.

M.Pt. 124.5–126.6° C.

¹H NMR (400 MHz, d₄-MeOH): δ 8.28 (1H, d, J=2.6 Hz), 8.16 (1H, d, J=4.6H (1H, d, J=2.5 Hz), 7.65 (1H, d, J=3.0 Hz), 7.49 (1H, dd, J=8.6, 2.5Hz), 7.38 (1H, dd, J=8.3, 4.8 Hz), 4.78–4.73 (2H, m), 4.65 (1H, quintet,J=3.4 Hz), 4.48 (2H, t, J=4.4 Hz), 4.29 (1H, dd, J=7.3, 5.3 Hz), 3.98(1H, dt, J=14.3, 3.1 Hz), 3.50 (1H, ddd, J=14.3, 11.2, 2.6 Hz), 3.31(d₄-MeOH), 3.30–3.24 (2H, m), 3.21–3.15 (2H, m), 2.77 (1H, dd, J=15.8,5.1 Hz), 2.53 (1H, dd, J=15.8, 7.1 Hz), 1.28 (3H, d, J=7.1 Hz, 0.00(TMS, reference).

¹³C NMR (100 MHz, d₄-MeOH): δ 179.64 (s), 176.38 (s), 157.02 (s), 152.32(s), 147.25 (s), 142.72 (d), 138.58 (d), 135.14 (d), 133.35 (d), 125.97(d), 123.40 (d), 69.67 (d), 68.00 (t), 65.78 (t), 48.61 (d), 48.32 (t),44.31 (t), 41.84(t), 40.20 (t), 14.80 (q), 0.00 (TMS, reference).

IR (diffuse reflectance) 3030 (s), 3009, 2970, 2469 (b), 2358, 2342 (b),2318 (b), 2303, 1571 (s), 1471, 1449, 1408, 1275 (s), 1233 (s), 1206(s), cm⁻¹.

HRMS (FAB) calcd for C₁₆H₂₁N₅O₂+H₁ 316.1773, found 316.1780.

[α]²⁵D=−21° (c 0.98, water).

Anal. Calcd for C₁₆H₂₁N₅O₂.C₄H₆O₅: C, 53.44; H, 6.05; N, 15.58. Found:C, 53.23; H, 6.08; N, 15.29.

Example 3B Preparation of(2R)-1-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,Succinate Salt

(2R)-1-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine(8.00 kg) obtained in Example 2B was dissolved in 24.0 kg of 1-propanolby heating to 60.5° C. The undissolved material was removed byfiltration. Succinic acid (1.30 kg) was dissolved in 23.9 kg of1-propanol by heating to 60.6° C. All undissolved material was removedby filtration. The procedure was repeated once with another 1.30 kg ofsuccinic acid and 23.9 kg of 1-propanol. All of the above solutions weremixed in a reactor. After mixing, the content's temperature was 53.9° C.The solution was heated to 78.3° C. Cooling was applied. At 40.3° C.,seeding with the title compound was done. Crystallization started afterthe seeding. The contents were stirred, while the temperature waslowered to 18.3° C. during the night. The product was isolated viafiltration under suction. The resulting product cake was washed with 10L of 1-propanol. The resulting semi-dry cake, weighing 17.2 kg was driedat 50° C./vakuum. After drying, the product, the title compound weighed9.16 kg (86%).

The preparation of the title compound has not been described in D1.

Melting temperature onset, 123° C.; thermal melting range, 116–132° C.

¹H NMR (500 MHz, DMSO-d₆): δ 1.12 (d, J=6.8 Hz), 1.28 (t, J=7.1 Hz),2.34 (s), 2.79 (m), 2.79 (m), 2.95 (m), 2.95 (m), 3.20 (dddd, J=13.7,11.5, 3.0, 1.1 Hz), 3.77 (dt, J=3.0, 13.7 Hz), 4.30 (q, J=7.1 Hz), 4.37(strong coupled), 4.49 (dqd, J=7.0, 6.8, 3.1 Hz), 4.62 (strong coupled),6.89 (dd, J=5.0, 7.8 Hz), 7.33 (dd, J=1.5, 7.8 Hz), 7.58 (d, J=2.8 Hz),7.69 (dd, J=1.5, 5.0 Hz), 7.77 (d, J=2.8 Hz).

¹³C-NMR (500 MHz, DMSO-d₆): δ 14.2, 14.5, 30.5, 40.5, 44.0, 47.9, 48.4,61.0, 64.0, 66.5, 116.8, 119.9, 130.3, 133.7, 137.2, 142.7, 146.3,149.9, 153.8, 174.5.

Anal. Calcd for C₁₈H₂₅N₅O₃. C₄H₆O₄: C, 55.34%; H, 6.54%; N, 14.67%.Found: C, 54.86; H, 6.75%; N, 13.85%.

Example 3C Preparation of(2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,phosphoric acid salt

(2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine(Example 2C) in water solution was added to the 198 L-glasslined reactorand heated to reflux. Water (30 L) was removed by distillation. Themixture was cooled to RT. before active charcoal (403.5 g) was added.The mixture was stirred for 30 minutes before transferred to the 100 Lglass-lined reactor using Teflon hose and a GAF-filter (containing apolypropylene filter bag) and a Millipore filter (containing a polyguardfilter cartridge). The hoses and filters were rinsed with water (10 L).To the water solution in the 100 L reactor phosphoric acid (3.83 kg) wasadded. The mixture was heated to reflux and water was distilled offuntil an 18 L solution of(2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazinein water/phosphoric acid remained. Ethanol (71 L) was added to thesolution while heating the mixture to reflux. All(2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazinewas in solution before the heat was turned off and the mixture allowedto cool to RT. A small amount of the solution was taken out to createseeds and the reaction-mixture was seeded when the temperature was60–68° C. The mixture was allowed to crystallize for 3 days (over aweekend, no cooling media was used) and the crystals were collected byfiltration using a Teflon filter nutch. The crystals were then dried ina vacuum oven for 2 days at 60° C. and at 100–200 mbar. 4.5 kg of thetitle compound was isolated. IP sample (HPLC) of the title compoundconfirmed the retention time for the title compound (tret=².² minutes).The yield of the title compound was 57% starting from2-(2-dimethylaminoethoxy)pyridin-3-ol.

By starting from(2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}-ethoxy)-2-pyrazinyl]-2-methylpiperazine(Example 2C) with a purity of 60–70%, the title compound was obtainedwith a purity of 99% in one crystallization step.

The preparation of the title compound has not been described in D1.

Melting temperature onset, 148.0° C. (extrapolated); thermal meltingrange, 140–168° C.

¹H NMR (500 MHz, DMSO-d₆): δ 1.21 (d, J=7.0), 2.60 (s), 2.92 (td,J=12.2, 3.2 Hz), 3.02 (dd, J=13.0, 2.6 Hz), 3.08 (dd, J=13.0, 4.2 Hz),3.16 (m), 3.17 (t, J=5.7 Hz), 3.38 (ddd, J=14.2, 11.6, 2.8 Hz), 3.94(dt, J=14.2, 3.2 Hz), 4.40(m), 4.52(m), 4.59 (m), 4.61 (m), 4.67 (ddd,J=12.3, 5.1, 3.5 Hz), 6.96 (dd, J=7.8, 5.0 Hz), 7.39 (dd, J=7.8, 1.4Hz), 7.62 (d, J=2.9 Hz), 7.71 (dd, J=5.0, 1.4 Hz), 7.80 (d, J=2.9 Hz).

¹³C-NMR (400 MHz, DMSO-d₆): δ 14.3, 38.6, 42.2, 43.4, 46.2, 46.7, 55.5,61.3, 64.0, 66.4, 117.7, 120.0, 130.9, 133.8, 137.0, 142.7, 145.7,150.0, 152.8.

HRMS m/z calcd for C₂₀H₃₀N₆O₃ (M)+402.2379, found 402.2366.

Anal. Calcd for C₂₀H₃₀N₆O₃. 3H₃PO₄: C; 34.49%; H, 5.64%; N, 12.07%; O,34.46%; P, 13.34%. Found: C, 37.20%; H, 6.0%; N, 12.5%; 0, 32.4%; P,12.1%.

Example 4 Preparation of (R)-2-methylpiperazine, L-tartrate

To the 1200 L reactor was added 60° C. racemic 2-methylpiperazine (100kg) from a drum. H₂O (240 L) was added, and the solution was cooled to13° C. To the 1200 L receiver was added L-tartaric acid (150 kg). H₂O(140 L) was added, and the slurry was stirred for 1 h 35 min untildissolution of the solids was complete. The L-tartaric acid solution wastransferred to the 1200 L reactor over 2 h while maintaining atemperature of 10–22° C. in the 1200 L reactor followed by a H₂O rinse(20 L). Ethanol (163 kg) was added to the 1200 L reactor, and thesolution was cooled to 2° C. The resulting slurry was stirred for 2 h at2° C., and filtered through a 36″ Nutsche filter sending the filtrateinto the 1200 L receiver. The 1200 L reactor and 36″ Nutsche filter werewashed with H₂O (200 L), and the solids were dried to yield 214 kg of12% ee (171% based on the title compound). These solids were rechargedto a clean 1200 L receiver and H₂O (630 L) was added to the 1200 Lreceiver, which was heated to 85° C. until all the solids had dissolved.The solution was filtered through an in-line filter (C) into the 1200 Lreactor, cooled to 5° C., and stirred for 2 h. The resulting slurry wasfiltered through a clean 36″ Nutsche filter sending the filtrate intothe 1200 L receiver. The 1200 L reactor and 36″ Nutsche filter werewashed with H₂O (200 L), and the solids were dried to yield 104 kg of93% ee (83% based on the title compound). These solids were recharged toa clean 1200 L receiver and H₂O (254 L) was added to the 1200 Lreceiver, which was heated to 85° C. until all the solids had dissolved.The solution was filtered through an in-line filter (C) into the 1200 Lreactor, cooled to 5° C., and stirred for 2 h. The resulting slurry wasfiltered through a clean 36″ Nutsche filter sending the filtrate intothe 1200 L receiver. The 1200 L reactor and 36″ Nutsche filter werewashed with H₂O (200 L), and the solids were dried to yield 92 kg of 99%ee (74% based on the title compound).

D1 does not describe the preparation of the title compound but makesreference to J. Med. Chem. 1990, 33, 1645–1656 (D2). The yield of thetitle compound according to D2, starting from racemic 2-methylpiperazinewas 35%.

M.Pt. 255.0–257.0° C.

¹H NMR (400 MHz, D₂O): δ 4.79 (D₂O, reference), 4.36 (2H, s), 3.73–3.64(4H, m), 3.43 (1H, td J=13.7, 3.0 Hz), 3.34 (1H, td, J=12.7, 3.1 Hz),3.17 (1H, dd, J=14.2 12.8 Hz), 1.41 (3H, d, J=6.1 Hz), 0.00 (TMS,reference).

¹³C NMR (100 MHz, D₂O): δ 178.46 (s), 73.91 (d), 49.02 (d), 49.00 (MeOH,reference), 45.82 (t), 40.56 (t), 40.10 (t), 15.42 (q).

IR (diffuse reflectance) 3426 (s), 3011 (s), 2999 (s), 2888 (s), 2785(s,b), 2740 (s,b), 2703 (s,b), 2649 (s,b), 2483 (s,b), 2483 (s,b), 2361(s), 2354, 2340, 2248, 1638 (s), cm⁻¹.

HRMS (FAB) calcd for C₅H₁₂N₂+H₁ 101.1079, found 101.1080.

[α]²⁵ _(D)=24° (c 1.00, water).

Anal. Calcd for C₄H₆O₆.C₅H₁₂N₂: C, 43.20; H, 7.25; N, 11.19. Found: C,41.25; H, 745; N, 10.71.

Example 5 Preparation of (R)-2-methylpiperazine

(R)-2-methylpiperazine, L-tartrate from Example 4 in H₂O (182 L), andBranched octanes (200 L) were added to a 4000 L reactor and stirreduntil dissolved. More branched octanes (530 L) were added to the 4000 Lreactor followed by 50% NaOH (1120 kg) at a temperature between 35° C.and 52° C. The solution was heated to 80° C. and stirred for 2 h. Thesolution was settled and the lower aqueous phase was transferred to the4000 L receiver. The solution in the 4000 L reactor was cooled to −21°C. and filtered onto a 48″ Nutsche filter sending the filtrate to a 1200L reactor. The 4000 L reactor and 48″ Nutsche filter were rinsed withbranched octanes (300 L). The solids were dried with 25° C. nitrogen andcollected to yield 24.9 kg (67%) of the title compound of NLT 99% ee asdetermined by chiral HPLC assay. The aqueous solution in the 4000 Lreceiver was adjusted to pH 8.4 with acetic acid (812 kg) beforedisposal.

The yield of the title compound according to D2, starting from(R)-2-methyl-piperazine, L-tartrate was 42%.

M.Pt. 91–93° C.

¹H NMR (400 MHz, CDCl₃): δ 2.97–2.68 (6H, m), 2.35 (1H, dd, J=11.7, 10.2Hz), 1.61 (2H, s), 1.00 (3H, d, J=6.7 Hz), 0.00 (TMS, reference).

¹³C NMR (100 MHz, CDCl₃): δ 54.14 (t), 51.89 (d), 47.43 (t), 46.46 (t),20.08 (q), 0.00 (TMS, reference). IR (mull) 3220 (s,b), 2819 (s), 2748,2042 (w), 1995 (w), 1981 (w), 1328, 1279, 1137, 1094, 960, 859 (s), 845(s), 795 (s), 621 (s), cm⁻¹.

HRMS (FAB) calcd for C₅H₁₂N₂+H₁ 101.1079, found 101.1080.

[α]²⁵ _(D)=−170 (c 0.85, CH₂Cl₂).

Anal. Calcd for C₅H₁₂N₂: C, 59.96; H, 12.07; N, 27.97. Found: C, 59.25;H, 11.71; N, 27.64.

Example 6 Preparation of (R)-3-methyl-1-tritylpiperazine

To the 1200 L reactor was dissolved (R)-2-methylpiperazine from Example5 (25 kg) in CH₃CN (319 kg) at 15° C. to 25° C. until dissolution wascomplete (10 min.) After cooling to 5° C. to 10° C. Et₃N (63 kg) wasadded. To the 1200 L receiver trityl chloride (69.5 kg) was dissolved inCH₂Cl₂ (106 kg) at 15° C. to 25° C. The solution in the receiver wastransferred to the reactor over 0.5 h with a CH₂Cl₂ rinse (27 kg), andthe solution was heated to 20° C. to 30° C. The reaction was monitoredby GLC and was complete in 1 h. The resulting slurry was cooled to 8° C.to 12° C., filtered onto a 48″ Nutsche filter, and rinsed with CH₃CN (40kg at 8° C. to 12° C.). The filter cake was dried using 50° C. to 55° C.nitrogen to afford 25.26 kg of the by-product Et₃NHCl (74% yield; easyto filter off the by-product). The filtrate was transferred to the 1200L reactor and cooled further to −8° C. to −10° C. for 1 h. The resultingslurry was filtered onto a 24″ Nutsche filter and rinsed with −8° C. to−10° C. CH₃CN (24 kg) sending the filtrate and rinse to the 1200 Lreceiver. The filter cake was dried with 50° C. to 55° C. nitrogen toafford another 2.98 kg Et₃NHCl (9% yield). The filtrate was transferredto the 1200 L reactor with a CH₃CN (10 kg) rinse, and distilled undervacuum to an oil of the title compound of 97.99% GC purity. The yieldwas quantitative.

M.Pt. 134–136° C.

¹H NMR (400 MHz, CDCl₃): δ 7.55–7.40 (6H, br s), 7.25 (6H, t, J=7.9 Hz),7.14 (3H, t, J=7.1 Hz), 3.21–3.13 (2H, m), 3.10–2.90 (1H, br s), 2.94(2H, t, J=13.0 Hz), 1.60 (1H, br s), 1.48 (1H, br s), 1.15 (1H, br s),0.94 (3H, d, J=6.1 Hz), 0.00 (TMS, reference).

¹³C NMR (100 MHz, CDCl₃): δ 129.41 (d), 127.46 (d), 125.96 (d), 125.83(s), 56.12 (t), 51.23 (d), 48.73 (t), 46.45 (t), 20.05 (q), 0.00 (TMS,reference).

IR (diffuse reflectance) 2964, 2835, 2483 (w), 2350 (w), 2339 (w), 1956(w), 1490, 1025, 909, 742 (s), 717, 710 (s), 703 (s), 697 (s), 629,cm⁻¹.

HRMS (EI) calcd for C₂₄H₂₆N₂ 342.2096, found 342.2101.

[α]²⁵ _(D)=−12 (c 1.00, CH₂Cl₂).

Anal. Calcd for C₂₄H₂₆N₂: C, 84.17; H, 7.65; N, 8.18. Found: C, 84.12;H, 7.64; N, 7.94.

Example 7 Preparation of(2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine

The product from Example 6 was dissolved in DMF (150 kg) at 25° C. Thesolution in the 1200 L reactor was cooled to 20° C. to 25° C. andtransferred into the 1200 L receiver with a DMF rinse (30 kg). AnhydrousK₂CO₃ (103 kg) was added to the 1200 L reactor. The solution in the 1200L receiver was transferred to the 1200 L reactor with a DMF rinse (30kg). The 2,3-dichloropyrazine (48.5 kg) was added with a DMF rinse (4L). The 1200 L reactor was heated to reflux at 127° C. to 133° C.Samples were taken every 12–18 h and monitored by GC. The reaction wascomplete in 41.5 h. The contents of the 1200 L reactor were cooled to35° C. to 45° C. and transferred onto a 48″ Nutsche filter sending thefiltrate sent to the 1200 L receiver. MtBE rinses (2×200 kg at 35° C. to45° C.) of the 1200 L reactor were transferred onto the 48″ Nutschefilter sending the rinses to the 1200 L receiver. The filtrate in the1200 L receiver was transferred to the 1200 L reactor with a MtBE rinse(50 kg). The solution in the 1200 L reactor was concentrated undervacuum to remove MtBE and DMF. MgSO₄ was added to a 48″ Nutsche (181 kg)and the 1200 L receiver (45 kg). MtBE (625 kg) was added to the 1200 Lreactor, heated to 40° C. to 45° C., and stirred to dissolve the titlecompound. The solution was cooled to 15° C. to 30° C. and transferredinto the 1200 L receiver with a MtBE rinse (100 kg). The slurry in the1200 L receiver was stirred for 3.5 h and filtered onto the 48″ Nutschefilter sending the filtrate into the 1200 L reactor. The 1200 L receiverwas rinsed with MtBE (2×250 kg at ˜15° C. to 30° C.) and transferred tothe 48″ Nutsche filter sending the rinses into the 1200 L reactor. Thefiltrate in the 1200 L reactor was distilled under vacuum to afford thetitle compound of 87.83% GC purity. The yield was quantitative.

¹H NMR (400 MHz, d₆-DMSO at 87° C.): δ 8.18 (1H, d, J=2.5 Hz), 7.89 (1H,d, J=2.1 Hz), 7.47 (6H, d, J=7.6 Hz), 7.31 (6H, 5, J=7.6 Hz), 7.18 (3H,t, J=7.4 Hz), 4.31–4.26 (1H, m), 3.66 (1H, ddd, J=12.4, 9.9, 2.5 Hz),3.48 (1H, br d,J=12.7 Hz), 2.72 (1H, br d, J=11.2 Hz), 2.59 (1H, br d,J=10.7 Hz), 2.49 (d₆-DMSO, reference), 2.14 (1H, br dd, J=11.2, 2.0 Hz),1.89 (1H, br t, J=9.9 Hz), 1.37 (3H, d, J=6.6 Hz).

¹³C NMR (100 MHz, d₆-DMSO at 87° C.): δ 153.85 (s), 141.51 (s), 139.79(d), 134.86 (d), 128.57 (d), 127.02 (d), 135.60 (d), 76.07 (s), 52.09(t), 50.84 (d), 47.68 (t), 44.40 (t), 39.52 (d₆-DMSO, reference), 15.39(q).

IR (diffuse reflectance) 2963 (s), 2350 (w), 2317 (w), 1959 (w), 1921(w), 1906 (w), 1501, 1488, 1465, 1443 (s), 1411 (s), 1143 (s), 1022,744, 708 (s), cm⁻¹.

HRMS (FAB) calcd for C₂₈H₂₇ClN₄+H₁ 455.2002, found 455.2004.

[α]²⁵ _(D)=−36° (c 0.98, CH₂Cl₂).

Anal. Calcd for C₂₈H₂₇ClN₄: C, 73.91; H, 5.98; N, 12.31; Cl, 7.79.Found: C, 74.26; H, 6.84; N, 10.74.

Example 8 Preparation of(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine

To the 1200 L reactor containing the product from Example 7 was addedIPA (707 kg). Stirring at reflux (77° C. to 83° C.) was continued untildissolution was complete. The solution in the 1200 L reactor wastransferred to the 4000 L reactor with a IPA rinse (100 kg) and heatedto reflux (77° C. to 83° C.). A 10% sulfuric acid solution (giving aclean reaction) was prepared in the 4000 L receiver by adding water (245L) and 98% H₂SO₄ (27 kg). The H₂SO₄ solution was stirred for 10 minutesat 20° C. to 60° C. and transferred to the 4000 L reactor whilemaintaining the 4000 L reactor temperature between 60° C. to 85° C. The4000 L receiver was rinsed with water (25 L) sending the rinse to the4000 L reactor. The 4000 L reactor was heated to reflux (77° C. to 83°C.). The reaction was monitored by GC and was complete in 30 min. Thecontents in the 4000 L reactor were cooled to 35° C. to 40° C. The IPAwas removed under vacuum distillation. Water (1265 L) and MtBE (511 kg)was added to the 4000 L reactor. After stirring and settling, theaqueous layer was transferred into the 4000 L receiver. The MtBE layerin the 4000 L reactor was disposed. MtBE (511 kg) was added to the 4000L receiver, the solution was stirred and settled for at least 15 min.The aqueous layer was transferred to the 4000 L reactor. The MtBE layerin the 4000 L receiver was disposed. The pH was adjusted to 9.5 to 10.5using 47% K₂CO₃ (206 kg) with a water rinse (50 L) of the add line.CH₂Cl₂ (2×765 L, 1×255 L) was used to extract the title compound fromthe 4000 L reactor sending the CH₂Cl₂ extractions into the 4000 Lreceiver. The organic solution in the 4000 L receiver was transferred tothe 4000 L reactor with a CH₂Cl₂ rinse (100 L). The CH₂Cl₂ was removedby distillation. Toluene (1000 L) was added to the 4000 L reactor andsubsequently removed by vacuum distillation to afford a toluene solutionof the title compound of 95.77% GC purity. The yield was quantitative.

Summarizing the steps of Examples 5–8, the yield of the product fromExample 8 was 67% starting from (R)-2-methylpiperazine, L-tartrate.According to D1, the yield of the same product was 60% starting from(R)-2-methylpiperazine, L-tartrate. The step described in D1corresponding to the process in Example 8 was performed in a mixture ofhot ethanol and 10% aqueous hydrochloric acid.

¹H NMR (400 MHz, CDCl₃): δ 8.12 (1H, d, J=2.6 Hz), 7.87 (1H, d, J=2.6Hz), 4.18–4.12 (1H, m), 3.39 (2H, t, J=3.6 Hz), 3.12 (1H, dd, J=12.2,3.6 Hz), 3.06 (1H, dt, J=12.2, 3.6 Hz), 3.02–2.95 (1H, m), 2.81 (1H, dd,J=12.2, 4.0 Hz), 1.90 (1H, br s), 1.21 (3H, d, J=6.6 Hz), 0.00 (TMS,reference).

¹³C NMR (100 MHz, CDCl₃): δ 155.15 (s), 140.85 (s), 139.93 (d), 135.15(d), 51.06 (d), 50.98 (t), 45.94 (t), 45.10 (t), 14.72 (q), 0.00 (TMS,reference).

IR (liq.) 2940, 2389 (w), 2149 (w), 1996 (w), 1556 (s), 1504 (s), 1459(s), 1440 (s), 1415 (s), 1367, 1330 (s), 1132 (s), 1107 (s), 1100 (s),1049 (s), cm⁻¹.

[α]²⁵ _(D)=−430 (c 0.59, CH₂Cl₂).

HRMS (FAB) calcd for C₉H₁₃ClN₄+H₁ 213.0907, found 213.0909.

Anal. Calcd for C₉H₁₃ClN₄: C, 50.83; H, 6.16; N, 26.34. Found: C, 50.48;H, 6.19; N, 26.47.

Example 9 Preparation of(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine, Hydrochloride

To a 200 L reactor was added the product from Example 8 in toluenesolution (ca 25 kg thereof in 93 kg solution) with an EtOAc rinse (10kg). Solvent was removed using vacuum until a volume of 35 L wasreached. To remove most of the toluene, EtOAc (2×90 kg) was added to the200 L reactor and distilled until a volume of 35 L was reached. EtOAc(90 kg) was added to the 200 L reactor and heated to reflux (78° C.).The slurry in the 200 L reactor was cooled to 55° C. to 60° C., filteredthrough a bag filter to remove solid impurities sending the filtrate tothe 200 L receiver. The 200 L reactor was rinsed with EtOAc (5 kg)sending the rinse into the 200 L receiver. The solution in the 200 Lreceiver was transferred to the 400 L reactor with an EtOAc rinse (5kg). 37% HCl (9.0 kg) was added to the 200 L receiver and rinsed withEtOAc (9 kg). The 37% HCl solution was transferred to the 200 L reactorwhile maintaining a temperature of 73° C. to 80° C. in the 200 Lreactor. The solution in the 200 L reactor was maintained at 72° C. for10 min. The solution was cooled to −25° C. to −30° C. for 2 h 45 min.The resulting slurry in the 200 L reactor was filtered onto an 18″Nutsche filter sending the filtrate into the 200 L receiver. The reactorand nutsche were rinsed with −25° C. EtOAc (3×45 kg) sending thefiltrate into drums. The filter cake was dried to afford 24.5 kg (79%)of the title compound of 98.4% GC purity. A 2^(nd) similar run gave 23.1kg for a total of 47.6 kg (77%).

M.Pt. 209.0–210.5° C.

¹H NMR (400 MHz, d₄-MeOH): δ 8.29 (1H, d, J=2.6 Hz), 8.07 (1H, d, J=2.6Hz), 4.83 (2H, br s), 4.30 (1H, sextet, J=5.8 Hz), 3.68–3.56 (2H, m),3.40 (1H, dd, J=14.2, 4.7 Hz), 3.37 (1H, m), 3.31 (1H, br s), 3.23 (1H,dd, J=12.7, 5.1 Hz), 1.30 (3H, d, J=6.6 Hz), 0.00 (TMS, reference).

¹³C NMR (100 MHz, d₄-MeOH): δ 155.45 (s), 143.28 (s), 141.90 (d), 138.91(d), 50.32 (d), 48.60 (t), 44.26 (t), 43.41 (t), 15.41 (q), 0.00 (TMS,reference).

IR (diffuse reflectance) 2934, 2802, 2781 (s), 2744 (s), 2717, 2684,2470, 2425, 2351 (w), 2335 (w), 2269 (w), 1453 (s), 1412 (s), 1148 (s),881 cm⁻¹.

HRMS (FAB) calcd for C₉H₁₃ClN₄+H₁ 213.0907, found 213.0912.

[α]²⁵ _(D=−24)° (c 0.92, water).

Anal. Calcd for C₉H₁₃ClN₄.HCl: C, 43.39; H, 5.66; N, 22.49. Found: C,43.48; H, 5.75; N, 22.37.

Example 10 Preparation of(2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,Fumarate

To a 400 L reactor was added a solution of the product from Example 2Ain MeOH (ca. 12.4 kg in 90 L solution) followed by a MeOH rinse (5 kg).The solution was distilled to a volume of 50 L. The fumaric acid (4.6kg) was added to the 400 L reactor using an addition funnel. The slurrywas stirred for 45 min at 25° C. to 30° C. until all the solidsdissolved. MtBE (133 kg) was slowly added, the resulting slurry wascooled to 30° C., and the solids were filtered onto an 18″ Nutschesending the filtrate into the 400 L receiver. The 400 L reactor and 18″Nutsche were rinsed with MtBE (16 kg) sending the rinse into the 400 Lreceiver. The title compound was dried and packaged to yield 12.3 kg(58%) of 97.4% GC purity. The product purity can be slightly improved byrepeating the crystallization.

M.Pt. 125.5–126.5° C.

¹H NMR (400 MHz, d₄-MeOH): δ 8.27 (1H, d, J=3.1 Hz), 8.15 (1H, d, J=4.5Hz), 7.78 (1H, d, J=2.6 Hz), 7.65 (1H, d, J=23.1 Hz), 7.48 (1H, dd,J=8.1, 2.5 Hz), 7.38 (1H, dd, J=8.5, 4.9 Hz), 6.69 (2H, s), 4.36 (4H, brs), 4.74 (2H, q, J=4.6 Hz), 4.69–4.63 (1H, m), 4.48 (1H, t, J=4.3 Hz),3.99 (1H, dt, J=11.7, 3.1 Hz), 3.51 (1H, ddd, J=14.7, 11.2, 3.0 Hz),3.30–3.26 (2H, m), 3.22–3.15 (2H, m), 1.28 (3H, d, J=6.7 Hz), 0.00 (TMS,reference).

¹³C NMR (100 MHz, d₄-MeOH): δ 171.20 (s), 156.98 (s), 152.27 (s), 147.16(s), 142.67 (d), 138.51 (d), 136.14 (d), 135.11 (d), 133.33 (d), 125.94(d), 123.39 (d), 67.97 (t), 65.75 (t), 48.16 (t), 48.54 (d), 44.17 (t),40.07 (t), 14.79 (q), 0.00 (TMS, reference).

IR (diffuse reflectance) 3047 (s), 3028 (s,b), 2985 (s,b), 2976 (s),2962 (s), 2350 (w), 2339 (w), 2318 (w), 2063 (w), 1990 (w), 1710 (s),1442 (s), 1261 (s), 1206 (s), 1190 (s), cm⁻¹.

[α]²⁵ _(D)=−20° (c 0.98, water).

Anal. Calcd for C₁₆H₂₁N₅O₂.C₄H₄O₄: C, 55.68; H, 5.84; N, 16.23. Found:C, 55.01; H, 5.88; N, 15.65.

Example 11 Comparison of the Properties of Different Salts of Example 2A

The following salts were prepared by Chemical development, Stockholm andKalamazoo and evaluated by Pharmaceutical Development, Nerviano:

-   (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine    (free base; see Example 2A)-   (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    L-malate (see Example 3A)-   (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    fumarate (see Example 10)-   (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    hydrochloride (see D1, Example 173)-   (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    acetate-   (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    benzoate-   (2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,    cinnamate.    Identification (NMR and Elementary Analysis)

Positive data for most salts, except for the free-base and thehydrochloride. NMR analysis was positive for the free-base. Thehydrochloride showed problems related to the stoichiometric ratio.

Crystallinity (X-rays)

Positive results for free base, acetate, benzoate, L-malate, andcinnamate were obtained. Most samples were substantially crystalline.Hydrochloride and especially fumarate came out to be of lowercrystallinity.

Hygroscopicity (DVS, Storage at RT/Different RHs and at 40° C./75% RH)

Positive results were obtained on benzoate, L-malate, and cinnamate.They showed lower hygroscopicity (<5% equilibrium moisture contents atRT/90% RH). Moisture-related effects on the bulk solid state propertiesof the benzoate salt were observed (cake formation and darkening) butwithout changes on the DSC pattern. Acetate and hydrochloride weredeliquescent (the former at RT/75% RH while the latter at highervalues). Fumarate was subjected to hydrate conversion upon exposition atRT/90% RH. Exposition to 40° C./75% RH showed good behavior of cinnamateand L-malate, recovered as powders showing substantially unchangedproperties.

Solubility (Water, pH 1.2 and pH 7.4 buffers)

Positive results were obtained for all salts (≅300 mg/ml FBE) with theexception of cinnamate whose solubility in water is about 8–10 mg/mlFBE.

Intrinsic Dissolution Rate (pH 1.2)

All results confirmed the solubility data. IDRs were about 10⁻¹ mgsec⁻¹cm⁻² while cinnamate had much lower dissolution rate (10⁻³ that means −2order of magnitude lower than the others). Acetate salt showed problemduring tablet preparation (sticking to the punch).

Chemical Stability (2 weeks at 65° C.)

Positive data for benzoate, L-malate, and cinnamate were obtained.Fumarate and acetate seemed to be the less stable salts either at RT/90%RH and at high temperature. Formation of the reaction product withfumaric acid was also observed. These samples showed unchanged DSCpatterns except for the acetate (peak broadening).

Polymorphism

The tested conditions (RT evaporation, cooling crystallization at −20°C. in different solvent or mixtures) did not show other polymorphs ofbenzoate and L-malate salts.

Manufacturing Method

Benzoate, L-malate, and cinnamate seemed to be easier to crystallizethan fumarate, hydrochloride and free base.

Toxicological Acceptability

There are few marketed drugs that are cinnamate salts and no muchinformation in literature. Oral LD_(50s) in rats are about 2500 mg/kgand 5 g/kg in mice.

Malic acid is an intermediate in the citric acid cycle and occursnaturally in apple and many fruits. It is FDA approved as food additive.A lot of drugs are approved in Europe and US as malate salts.

In summary, of the salts examined above,(2R)-methyl-1-{3-[2-(3-pyridinyloxy)ethoxy]-2-pyrazinyl}piperazine,L-malate seems to be the best choice of the salts examined due to itshigh crystallinity, low hygroscopicity, high chemical stability and lowtoxicity.

Example 12 Comparison of the Properties of Different Salts of Example 2B

The following salts have been prepared:

-   (2R)-1-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine    (free base, see Example 2B)-   (2R)-1-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,    acetate-   (2R)-1-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,    fumarate (see D1, Example 200)-   (2R)-1-(3-{2-[(2-ethoxy-3-pyridinyl)oxy]ethoxy}-2-pyrazinyl)-2-methylpiperazine,    succinate (see Example 3B).    Crystallinity (Powder X-ray Diffraction)

For the succinate salt, the degree of crystallinity was very high. Thedegree of crystallinity decreased in the ordersuccinate>acetate>fumarate.

Thermal Properties

For the free base and the acetate salt the melting temperature onset waslow (81° C. and 96° C., respectively). These low melting points can bedrawbacks in future development work. For the succinate and fumaratesalts the thermal properties were fair since the extrapolated meltingtemperature onset was 123° C. and 149° C., respectively.

Hygroscopicity

All but the acetate salt had acceptable properties with repect tohygroscopicity. The acetate salt was very hygroscopic and showed apronounced hysteresis at high values of relative humidity.

Solubility and Intrinsic Dissolution Rate

The solubility of the succinate salt, in all investigate media, was atleast 250 mg/ml.

For the fumarate salt the solubility was >93 mg/ml in 0.9% w/w NaCland >68 mg/ml in phosphate buffer at pH 7.4. Hence, the solubility ofsuccinate was in all instances higher than the fumarate salt.

The intrinsic dissolution rate studies indicated the dissolution rate toincrease according to the order base<fumarate<succinate.

In conclusion, with the respect to the solubility and the intrinsicdissolution rate, the succinate salt proved to have the most favourablequalities of the salts and the free base studied.

Impurities

Analysis (LC-UV-MS) of the fumarate salt revealed the presence of afumarate adduct (˜1%) and the formation of dimers of the free base(0.2%). The fumarate adduct may be a Michael adduct between thepiperazine ring and fumaric acid.

Conclusion

The succinate salt hade the overall best state properties, goodcrystallinity, a relatively high melting point, a high solubility and ahigh intrinsic dissolution rate. The acetate salt proved to be bothhygroscopic and to have a low melting range. The solubility, intrinsicdissolution rate and the degree of crystallinity of the fumarate saltwas inferior to that of the succinate salt. In view of the properties ofthe different salts investigated the best candidate for furtherdevelopment is the succinate salt.

Example 13 Comparison of the Properties of Different Salts of Example 2C

The following salts have been prepared:

-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine    (free base; see Example 2C)-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    phosphoric acid salt (see Example 3C)-   (2R)—    1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    acetate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    citrate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    edeteate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    oxalate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    succinate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    D-tartrate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    1,3,5-benzenetricarboxylate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    galactareate (mucic acid salt)-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    1,5-naphthalenedisulfonate-   (2R)-1-[3-(2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy}ethoxy)-2-pyrazinyl]-2-methylpiperazine,    terephthalate.    Crystallinity (Powder X-ray Diffraction)

The acetate- and the oxalate salt had a high degree of crystallinitywhilst the crystallinity of the succinate salt and the phosphoric acidsalt ranged from predominantely crystalline to moderately crystallinity.The D-tartrate salt had a low degree of crystallinity. Two salts,edeteate and citrate proved to be practically amorphous. The free baseis a viscous oil at ambient conditions. The benzenetricarboxylate,naphthalenedisulfonate and terephtalate were predominantly crystalline,whilst the galactareate was partially amorphous.

Hygroscopicity

The acetate, citrate, edeteate, succinate and D-tartrate salts proved tobe very hygroscopic and deliquescent. Also the free base washygroscopic. The hygroscopicity of the the oxalate and phosphoric acidsalt was low. The hygroscopicity of the benzenetricarboxylate,naphthalenedisulfonate and terephthalate was low, moderate and hight(deliquescent), respectively.

Solubility

The solubility of the phosphoric acid salt was, in all investigatedmedia, not less than 590 mg/ml. Preliminary studies indicated thebenzenetricarboxylic acid to have a solubility of >19 mg/ml in SGF(simulated gastric fluid without enzymes; pH of filtrate 2.9), 11 mg/mlin SIF (simulated intestinal fluid without enzymes; pH of filtrate 4.2)and in purified water 4 mg/ml (pH of filtrate 3.6). The solubility ofthe naphthalenedisulfonate was high >540 mg/ml. Preliminary studies ofthe solubility of the terephthalate salt in purified water indicated thesolubility to be low (<1 mg/ml).

Toxicological Acceptability

Regarding the oxalate salt although its solid state properties are goodit was deemed inappropriate due to toxicological reasons. Thebenzenetricarboxylate salt had the overall most promising solid stateproperties but the solubility was lower than for the phosphoric acidsalt and requires a toxicological evaluation. The phosphoric acid saltwas deemed to be the best choice of the salts regarding highcrystallinity, low hygroscopicity, high solubility, and low toxicity.

1. A process for the preparation of a pharmaceutically acceptable saltof a compound of the general formula (I):

comprising the steps of: (i) O-alkylating a 3-pyridinol derivative ofthe general formula (II) or the corresponding hydrochloride:

to give another 3-pyridinol derivative of the general formula (III):

(ii) reacting the 3-pyridinol derivative of the general formula (III)with (2R)-1-(3-chloro-2-pyrazinyl)- 2-methylpiperazine of the formula(IV) in the presence of an alkali metal tert-butoxide or an alkali earthmetal tert-butoxide,

to give a compound of the general formula (I):

(iii) converting the compound of the general formula (I) to apharmaceutically acceptable salt thereof by treatment with apharmaceutically acceptable organic or inorganic acid, wherein each ofR₁, R₂, R₃, and R₄, independently, is hydrogen, halogen, C₁–C₆-alkyl,C₁–C₆-alkoxy, and di-C₁–C₆-alkylamino-C₂–C₆-alkoxy.
 2. The processaccording to claim 1, wherein(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV) isprepared by: (iv) acidification of racemic 2-methylpiperazine of theformula (VI):

with L-tartaric acid and fractional crystallization to give(R)-2-methylpiperazine, L-tartrate of the formula (VII):

(v) basification of (2R)-2-methylpiperazine, L-tartrate of the formula(VII) to give (R)-2-methylpiperazine of the formula (VIII):

(vi) tritylation of (R)-2-methylpiperazine of the formula (VIII) to give(R)-3-methyl-1-tritylpiperazine of the formula (IX):

(vii) condensation of (R)-3-methyl-1-tritylpiperazine of the formula(IX) with 2,3-dichloropyrazine to give(2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine of the formula(X):

(viii) detritylation of(2R)-1-(3-chloro-2-pyrazinyl)-2-methyl-4-tritylpiperazine of the formula(X) to give (2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of theformula (IV), (ix) and conversion of(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV) toa suitable acid addition salt.
 3. The process according to claim 1,wherein the alkali metal tert-butoxide is potassium tert-butoxide. 4.The process according to any one of claims 1 to 3, wherein step (ii) isperformed in a solvent system comprising tetrahydrofuran.
 5. The processaccording to claim 2, wherein step (iv) is performed by using water andethanol as solvents.
 6. The process according to claim 2, wherein step(v) is performed by using a hydroxide as a base.
 7. The processaccording to claim 2, wherein step (vi) is performed with tritylchloride in the presence of triethylamine.
 8. The process according toclaim 2, wherein step (vii) is performed in the presence of an alkalimetal carbonate or an alkali earth metal carbonate, with dimethylformamide as a solvent.
 9. The process according to claim 2, whereinstep (viii) is performed in 10% sulfuric acid in isopropanol.
 10. Theprocess of claim 2, wherein the salt formed in step (ix) is ahydrochloride salt.
 11. The process of claim 1, wherein(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine of the formula (IV) isin the form of an acid addition salt.